The research proposed here is an ongoing inquiry into the immunogenicity, host response and natural history of human melanoma and its precursor lesions. Central to this effort is a large, well studied group of patients with melanoma and a variety of its precursors. This research utilizes both patient-derived cell lines and monoclonal antibodies directed to melanoma-associated antigens. With these materials, we have found a fundamental difference in the behavior of cell lines established from biologically early melanoma and advanced disease. Cells cultured from early melanoma (in "radial growth phase") stimulate the proliferation of autologous lymphocytes. These, in turn, generate autologous tumor cytotoxicity and produce relevant lymphokines (e.g., Gamma-interferon). Expression of HLA-DR histocompatibility antigens is necesssary but insuffcient of the melanoma cells to stimulate. Melanoma cells derived from advanced disease ("vertical growth phase" and metastases) are not stimulatory. Current and proposed studies are directed to: 1) identifying the antigen(s) on melanoma which, in concert with HLA-DR, provoke lymphocyte stimulation or, conversely, which are lost from those cells which do not stimulate; 2) characterizing the phenotype and function of host cells, particularly T cells, responding in vitro to autologous melanoma; 3) identifying the antigen(s) on melanoma which are the targets of specifically cytotoxic T cells; and 4) extending studies of lymphocyte stimulation and the responsible antigens to cells cultured from melanoma precursors. These studies should contribute to an understanding of the role of host cellular imunity in the developmental biology of melanoma. Such studies are of general importance to tumor immunology as melanoma (because of its easy detection and accessibility in the skin) can be investigated while the early, and presumably most important, host-tumor interactions are taking place. An understanding of these interactons should lead to strategies to manipulate the immune response to melanoma and may well lead to the development of novel therapies.